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Part 1 of 4
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Program Editors
Ralph Anthony DeFronzo, MD Professor of Medicine and
Chief of the Diabetes Division
University of Texas Health
Science Center
Audie L. Murphy Memorial Veterans Hospital
San Antonio, Texas, USA
Jaime A. Davidson, MD President, Worldwide Initiative
for Diabetes Education
Clinical Professor of Internal Medicine
Division of Endocrinology
University of Texas Southwestern
Medical School
Dallas, Texas, USA
Jaime A. Davidson, MD President, Worldwide Initiative
for Diabetes Education
Clinical Professor of Internal Medicine
Division of Endocrinology
University of Texas Southwestern
Medical School
Dallas, Texas, USA
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Faculty
Professor Rury HolmanProfessor of Diabetic Medicine
Honorary Consultant Physician
Diabetes Trials Unit
University of Oxford
Oxford, United Kingdom
Professor Stefano Del PratoProfessor of Endocrinology and Metabolism
School of Medicine
University of Pisa
Pisa, Italy
Professor Allan VaagChief Physician
Steno Diabetes Center
Gentofte, Denmark
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SGLT2 InhibitionSGLT2 Inhibition
A Novel Treatment Strategy for Type 2 DiabetesA Novel Treatment Strategy for Type 2 Diabetes
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The Ominous OctetThe Ominous Octet
Islet -cell
ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion
NeurotransmitterNeurotransmitterDysfunctionDysfunction
Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake
Islet -cell
IncreasedIncreasedGlucagon SecretionGlucagon SecretionIncreasedIncreasedGlucagon SecretionGlucagon Secretion
IncreasedIncreasedLipolysisLipolysisIncreasedIncreasedLipolysisLipolysis
Increased GlucoseIncreased GlucoseReabsorptionReabsorptionIncreased GlucoseIncreased GlucoseReabsorptionReabsorption
IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP
DecreasedDecreasedIncretin EffectIncretin Effect
DecreasedDecreasedIncretin EffectIncretin Effect
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Renal Glucose Reabsorption Renal Glucose Reabsorption in Type 2 Diabetesin Type 2 Diabetes
• Sodium-glucose cotransporter 2 (SGLT2) plays a role in renal glucose reabsorption in proximal tubule
• Renal glucose reabsorption is increased in type 2 diabetes
• Selective inhibition of SGLT2 increases urinary glucose excretion, reducing blood glucose
Wright EM, et al. J Intern Med. 2007;261:32-43.
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SGLT1SGLT1
(180 L/day) (900 mg/L)=162 g/day(180 L/day) (900 mg/L)=162 g/day
10%10%
GlucoseGlucose
No GlucoseNo Glucose
S1S1
S3S3
Renal Handling of GlucoseRenal Handling of Glucose
SGLT2
90%
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GLUT2GLUT2 AMG UptakeAMG Uptake
NGT T2DM NGT T2DM
AMG=methyl--D-[U14C]-glucopyranoside; CPM=counts per minute.
Rahmoune H, et al. Diabetes. 2005;54:3427-3434.
SGLT2SGLT2
NGT T2DM0
2
6
8
0
500
1000
1500
2000
No
rmal
ized
Glu
cose
T
ran
spo
rter
Lev
els
CP
M
Increased Glucose Transporter Proteins Increased Glucose Transporter Proteins and Activity in Type 2 Diabetesand Activity in Type 2 Diabetes
P<0.05
4
P<0.05
P<0.05
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5 mmol/L5 mmol/L
FastingFastingPlasma GlucosePlasma Glucose
MuscleMuscle
Normal Glucose HomeostasisNormal Glucose Homeostasis
FatFat
LiverLiver
PancreasPancreas
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FastingFastingPlasma GlucosePlasma Glucose
Pathophysiology of Type 2 DiabetesPathophysiology of Type 2 Diabetes
10 mmol/L10 mmol/L
Islet -cell
Impaired Insulin Impaired Insulin SecretionSecretionImpaired Insulin Impaired Insulin SecretionSecretion
Insulin Insulin ResistanceResistance
Increased Increased HGPHGP
5 mmol/L5 mmol/L
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Rationale for SGLT2 InhibitorsRationale for SGLT2 Inhibitors
• Inhibit glucose reabsorption in the renal proximal tubule
• Resultant glucosuria leads to a decline in plasma glucose and reversal of glucotoxicity
• This therapy is simple and nonspecific
• Even patients with refractory type 2 diabetes are likely to respond